Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy
Background: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (<i>IDH</i>) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining <i>IDH</i> status (wild type (WT) and...
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| Format: | Article |
| Language: | English |
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MDPI AG
2024-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/16/2/247 |
| _version_ | 1797344459557437440 |
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| author | Karen Schoedel Tanya Heim Anette Duensing Ines Lohse Laura Presutti Rebekah Belayneh Sumail Bhogal Anya Singh-Varma Alexander Chang Uma Chandran Daniel Marker Heather Szabo-Rogers Kurt Weiss |
| author_facet | Karen Schoedel Tanya Heim Anette Duensing Ines Lohse Laura Presutti Rebekah Belayneh Sumail Bhogal Anya Singh-Varma Alexander Chang Uma Chandran Daniel Marker Heather Szabo-Rogers Kurt Weiss |
| author_sort | Karen Schoedel |
| collection | DOAJ |
| description | Background: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (<i>IDH</i>) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining <i>IDH</i> status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. Methods: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing for <i>IDH1</i> and <i>IDH2</i> mutations (<i>n</i> = 47) and RNA sequencing via Nextseq 2000 (<i>n</i> = 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. Results: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on available <i>IDH</i> status, we evaluated 15 <i>IDH</i> WT and 32 <i>IDH</i> mutant tumors as part of this dataset. Out of 15 <i>IDH</i> WT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed in <i>IDH</i> WT tumors compared to <i>IDH</i> mutant tumors. Furthermore, <i>IDH</i> WT and <i>IDH</i> mutant tumors were transcriptomically distinct in the IPA and GSEA, with <i>IDH</i> mutant tumors showing increased activity in methylation pathways and endochondral ossification, while <i>IDH</i> WT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR in <i>IDH</i> WT tumors, but not in <i>IDH</i> mutants. SATB2 was expressed in <i>IDH</i> mutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (<i>p</i> = 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (<i>p</i> = 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (<i>p</i> = 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients with <i>IDH</i> WT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. Conclusions: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by <i>IDH</i> status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on <i>IDH</i> status, and implies different treatment targets. |
| first_indexed | 2024-03-08T11:02:55Z |
| format | Article |
| id | doaj.art-0d5d0fcfb25948a7aa75ad6784d7bd1c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-08T11:02:55Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0d5d0fcfb25948a7aa75ad6784d7bd1c2024-01-26T15:33:35ZengMDPI AGCancers2072-66942024-01-0116224710.3390/cancers16020247Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and TherapyKaren Schoedel0Tanya Heim1Anette Duensing2Ines Lohse3Laura Presutti4Rebekah Belayneh5Sumail Bhogal6Anya Singh-Varma7Alexander Chang8Uma Chandran9Daniel Marker10Heather Szabo-Rogers11Kurt Weiss12Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USADepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USADepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USADepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USASchool of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USADepartment of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA 15206, USADepartment of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USADepartment of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E2, CanadaDepartment of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15232, USABackground: Grade 2 and 3 and dedifferentiated chondrosarcomas (CS) are frequently associated with isocitrate dehydrogenase (<i>IDH</i>) mutations and often exhibit a poor clinical outcome. Treatment is limited mainly to surgery. Defining <i>IDH</i> status (wild type (WT) and mutant) and the associated transcriptome may prove useful in determining other therapeutic options in these neoplasms. Methods: Formalin-fixed paraffin-embedded material from 69 primary and recurrent grade 2, 3 and dedifferentiated CS was obtained. DNA sequencing for <i>IDH1</i> and <i>IDH2</i> mutations (<i>n</i> = 47) and RNA sequencing via Nextseq 2000 (<i>n</i> = 14) were performed. Differentially expressed genes (DEGs) were identified and used to predict aberrant biological pathways with Ingenuity Pathway Analysis (IPA) software (Qiagen). Gene Set Enrichment Analyses (GSEA) using subsets C3, C5 and C7 were performed. Differentially expressed genes were validated by immunohistochemistry. Outcome analysis was performed using the Wilcoxon test. Results: A set of 69 CS (28 females, 41 males), average age 65, distributed among femur, pelvis, humerus, and chest wall were identified from available clinical material. After further selection based on available <i>IDH</i> status, we evaluated 15 <i>IDH</i> WT and 32 <i>IDH</i> mutant tumors as part of this dataset. Out of 15 <i>IDH</i> WT tumors, 7 involved the chest wall/scapula, while 1 of 32 mutants arose in the scapula. There were far more genes overexpressed in <i>IDH</i> WT tumors compared to <i>IDH</i> mutant tumors. Furthermore, <i>IDH</i> WT and <i>IDH</i> mutant tumors were transcriptomically distinct in the IPA and GSEA, with <i>IDH</i> mutant tumors showing increased activity in methylation pathways and endochondral ossification, while <i>IDH</i> WT tumors showed more activity in normal matrix development pathways. Validation immunohistochemistry demonstrated expression of WT1 and AR in <i>IDH</i> WT tumors, but not in <i>IDH</i> mutants. SATB2 was expressed in <i>IDH</i> mutant tumors and not in WT tumors. Outcome analysis revealed differences in overall survival between mutant and WT tumors (<i>p</i> = 0.04), dedifferentiated mutant and higher-grade (2, 3) mutant tumors (<i>p</i> = 0.03), and dedifferentiated mutant and higher-grade (2, 3) WT tumors (<i>p</i> = 0.03). The longest survival times were observed in patients with higher-grade WT tumors, while patients with dedifferentiated mutant tumors showed the lowest survival. Generally, patients with <i>IDH</i> WT tumors displayed longer survival in both the higher-grade and dedifferentiated groups. Conclusions: Grade 2, 3 and dedifferentiated chondrosarcomas are further characterized by <i>IDH</i> status, which in turn informs transcriptomic phenotype and overall survival. The transcriptome is distinct depending on <i>IDH</i> status, and implies different treatment targets.https://www.mdpi.com/2072-6694/16/2/247chondrosarcomaRNA sequencingisocitrate dehydrogenasegenomics |
| spellingShingle | Karen Schoedel Tanya Heim Anette Duensing Ines Lohse Laura Presutti Rebekah Belayneh Sumail Bhogal Anya Singh-Varma Alexander Chang Uma Chandran Daniel Marker Heather Szabo-Rogers Kurt Weiss Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy Cancers chondrosarcoma RNA sequencing isocitrate dehydrogenase genomics |
| title | Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy |
| title_full | Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy |
| title_fullStr | Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy |
| title_full_unstemmed | Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy |
| title_short | Grade 2, 3 and Dedifferentiated Chondrosarcomas: A Comparative Study of Isocitrate Dehydrogenase-Mutant and Wild-Type Tumors with Implications for Prognosis and Therapy |
| title_sort | grade 2 3 and dedifferentiated chondrosarcomas a comparative study of isocitrate dehydrogenase mutant and wild type tumors with implications for prognosis and therapy |
| topic | chondrosarcoma RNA sequencing isocitrate dehydrogenase genomics |
| url | https://www.mdpi.com/2072-6694/16/2/247 |
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